The goal of this Project is to develop and implement novel, high resolution structural and functional MRI, to identify the earliest apparent brain changes in subjects at risk for developing AD. Specifically, we will examine young and older control subjects with and without the APOE-4 allele, and patients with MCI and mild AD, in a cross-sectional comparison of age-related changes in the brain, and in a 2-year longitudinal follow-up, using MRI acquisition and analysis tools recently developed in our laboratory. We will focus on changes in the structure and function in the hippocampus, where ample evidence indicates the pathological process leading to AD arises. Our aims cover 3 general goals: 1) to identify subtle changes in brain structure, particularly in entorhinal cortex and in anterior hippocampus, in at-risk and cognitively declining subjects 2) to identify abnormalities in functional activity in individual sub-regions of the nippocampal complex using different memory paradigms, and 3) to develop integrative models for determining the relationship between these functional and structural MRI markers and PET markers of amyloid burden (based on [18F]DDNP) and nippocampal 5HT1A receptor activity (based on [18F]MPPF PET). For structural MRI, we will acquire small voxel T1 weighted volumetric scans, on which we will conduct voxel-based parametric maps of longitudinal change in grey matter distribution, as well as grey-matter segmented region of interest analysis to be shared with the other projects. Additionally, we will collect very high in-plane resolution images of the hippocampus (.3 mm) to serve as a basis for studies of 1) gray matter thickness in entorhinal cortex, individual CA fields, subiculum and parahippocampal gyrus; 2) sulcal variability maps, measuring small displacements in sulci secondary to subtle tissue loss; and 3) unfolded "flat maps" of the hippocampus to discriminate among subregions, in combination with 4) high resolution BOLD FMRI of the hippocampus during episodic encoding, retrieval, and novelty encoding paradigms. We will integrate these structural and functional imaging measures of regional nippocampal integrity with [18F]DDNP and [18F]MPPF maps to determine how amyloid burden relates to hippocampal morphometry and function, and how this relationship changes dynamically in genetically at-risk individuals. These studies will enable us to develop highly sensitive predictive formulas for identifying those most likely to show decline, and will help us to understand the pathophysiology of AD as it relates to neural loss and amyloidopathy.